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\begin{document}

\title{Post Radiation Middle Ear Effusion in NPC Patients - Analysis of
Patient, Tumor and Radiation Factors}



\author[1]{Igor Vainer}%
\author[1]{Sharon Tzelnick}%
\author[2]{noga kurman}%
\author[3]{Aron Popovtzer}%
\author[1]{Ethan Soudry}%
\affil[1]{Rabin Medical Center}%
\affil[2]{Tel Aviv University Sackler Faculty of Medicine}%
\affil[3]{Hadassah University Medical Center Sharett Institute of Oncology}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Introduction: The purpose of this study was to investigate whether
patient, tumor and radiation therapy factors are associated with
development of middle ear effusion (MEE) in nasopharyngeal carcinoma
(NPC) patients. Methods: A retrospective review of NPC patients treated
between January 2000 and June 2018 at Rabin Medical Center. Patient
factors, tumor factors, radiation doses and radiation fields were
collected and outlined if needed (middle ear, eustachian tube (ET),
tensor veli palatini (TVP) and levator palatini (LVP) muscles), then
analyzed and compared between patients with MEE and those without and
between sides in patients with unilateral MEE. Results: 73 patients were
enrolled. Most were males (71.2\%) with advanced stage diseases (78\%).
At the time of diagnosis 14 patients (19.2\%) presented with MEE and in
18 (24.6\%) patients post radiation MEE was observed (15 ipsilateral to
the tumor and 3 bilateral). Tumor stage, histology and laterality were
not associated with development of MEE. Comparison of mean radiation
field dosages including - gross target volume (GTV), clinical target
volume (CTV) and patient target volume (PTV) showed no association with
post radiation MEE. In addition, no difference was found in the
radiation doses to the middle ear, ET or the LVP nor the TVP between
ears with and without MEE. Conclusions: Postirradiation MEE remains a
common adverse effect in NPC patients. Surprisingly, tumor stage, tumor
laterality and histology were not associated with MEE. Similar findings
were observed for total radiation doses and specific doses to the middle
ear, ET and ET muscles.%
\end{abstract}%



\sloppy


\textbf{Abstract}

Introduction:~ The purpose of this study was to investigate whether
patient, tumor and radiation therapy factors are associated with
development of middle ear effusion (MEE) in nasopharyngeal carcinoma
(NPC) patients.

Methods:~A retrospective review of NPC patients treated between January
2000 and June 2018 at Rabin Medical Center.

Patient factors, tumor factors, radiation doses and radiation fields
were collected and outlined if needed (middle ear, eustachian tube (ET),
tensor veli palatini (TVP) and levator palatini (LVP) muscles), then
analyzed and compared between patients with MEE and those without and
between sides in patients with unilateral MEE.

Results: 73 patients were enrolled. Most were males (71.2\%) with
advanced stage diseases (78\%). At the time of diagnosis 14 patients
(19.2\%) presented with MEE and in 18 (24.6\%) patients post radiation
MEE was observed (15 ipsilateral to the tumor and 3 bilateral). Tumor
stage, histology and laterality were not associated with development of
MEE. Comparison of mean radiation field dosages including - gross target
volume (GTV), clinical target volume (CTV) and patient target volume
(PTV) showed no association with post radiation MEE. In addition, no
difference was found in the radiation doses to the middle ear, ET or the
LVP nor the TVP between ears with and without MEE.

Conclusions:~Postirradiation MEE remains a common adverse effect in NPC
patients.~Surprisingly, tumor stage, tumor laterality and histology were
not associated with MEE. Similar findings were observed for total
radiation doses and specific doses to the middle ear, ET and ET muscles.



\emph{Key points --}

\begin{itemize}
\tightlist
\item
  This study aimed to investigate whether patient, tumor, and radiation
  therapy factors are associated with the development of middle ear
  effusion (MEE) in patients with nasopharyngeal carcinoma (NPC).
\item
  The retrospective review included patients treated between January
  2000 and June 2018 at a tertiary medical center. Patient and tumor
  factors, radiation doses, and radiation fields were collected and
  analyzed between patients with and without MEE and between sides in
  patients with unilateral MEE.
\item
  The study found that post-irradiation MEE was a common adverse effect
  in NPC patients, and tumor stage, histology, and laterality were not
  associated with MEE.
\item
  Additionally, no difference was found in the radiation doses to the
  middle ear, Eustachian tube, Levator veli palatine, or Tensor veli
  palatine muscles between ears with and without MEE.
\item
  The study suggests that IMRT may reduce otologic complications in NPC
  patients. The study provides important information on risk factors for
  MEE in NPC patients, which can help inform management strategies.
\end{itemize}

\emph{Key words} -- Nasopharyngeal Carcinoma, Middle ear effusion,
Levator veli-palatini, Tensor veli-palatine, Radiotherapy

Conflict of Interest: The authors have no conflicts of interest to
disclose.

Funding Source -- None.

\textbf{Introduction}

Nasopharyngeal carcinoma (NPC) is the most common type of tumor
originating in the epithelium of the nasopharynx and a distinct tumor of
head and neck region which is primarily treated with external beam
radiation therapy, with or without concurrent cisplatin
chemotherapy.\textsuperscript{1,2}~External beam radiation to the head
and neck region is notorious for its otologic complications including
external otitis, otitis media, sensorineural hearing loss (SNHL) and
osteoradionecrosis of the temporal bone.\textsuperscript{3,4} Post
irradiation middle ear effusion (MEE), is associated with conductive
hearing loss. If not identified and managed properly, it may progress to
full atelectasis of the ear drum associated ossicular bone erosion,
hearing loss deterioration and
cholesteatoma.\textsuperscript{5,6}~Therefore, evaluation of NPC
patients for the presence of MEE is mandatory.

In the late 1990's new radiation modalities were introduced to decrease
the radio-toxicity related to the radiation therapy (RT), one of which
is intensity-modulated radiotherapy (IMRT).\textsuperscript{7,8}~IMRT is
superior to the traditional 2D radiation due to its three-dimensional
properties which allow a more precise planning of the irradiated tumor
volume, sparing non-involved regions. As such, in patients with NPC it
may allow reducing the otologic complications.\textsuperscript{9,10} The
main structures associated with normal middle ear function are the
Eustachian tube (ET), the Levator veli-palatini (LVP) and Tensor
veli-palatine (TVP) muscles which function as the ET dilators, and are
therefore crucial for its normal function and patency.

The primary objective of this study was to perform a comprehensive
analysis of patient, tumor and treatment parameters as risk factors for
post radiation MEE in NPC patients. Specifically, irradiation parameters
of the middle ear, ET, TVP and LVP regions were investigated as well as
potential contributors.

\textbf{Methods}

\emph{Patients}

The study was reviewed and approved by the local Institutional Review
Board (IRB). We conducted a retrospective review of the medical database
of our tertiary medical center for all patients treated for NPC between
2000-2018.

Inclusion criteria were adult patients (age\textgreater{}18 years) who
had at least one year of follow up. Patients with primary sinonasal
malignancies were excluded.

Data retrieved included patient demographics as well as treatment
modalities, imaging, tumor pathology and follow up data.

\emph{Treatment protocol}

The treatment protocol in our institution for patients with NPC includes
radiation or chemoradiation therapy (CRT) according to the NCCN
guidelines. Until 2008 2D/3D -CRT was the radiation modality available
in our institution. Since 2008, intensity modulated radiation therapy
(IMRT) has been the modality of choice.

A computed tomography simulation was used to plan treatment in all
cases. Tumor volumes were outlined, and a computed tomography--based
display of the isodoses was recorded to confirm adequate target
coverage. The radiation field included the gross tumor in the
nasopharynx and neck, elective nodal stations, with a planning target
volume (PTV) of a 0.3-cm margin. In our study we examined in particular
the radiation doses of the middle ear, Eustachian tube, Levator veli
palatine and Tensor veli palatine muscles. Each radiation plan was
accessed in Aria\textsuperscript{TM} radiation planning software and the
studied structures were delineated on each axial section of the
simulation imaging. Corrections were later made on the sagittal and
coronal sections of the imaging for a more precise outlining of the
structures. (Figure 1.)

\emph{Otitis media with effusion diagnosis and follow up}

Middle ear fluids were observed either by otoscopic examination -
oromicroscopy or imaging (CT scan or MRI) follow up. MEE was suspected
when otoscopy discovered a decreased motility of the tympanic mebrane,
an air-fluid level or amber color change within the middle ear cavity
which were confirmed by detecting opacification of the middle ear and
mastoid air cells on imaging of the patient which were also examined.

\emph{Statistical analysis}

Data was analyzed using the SPSS statistical software version 25.0 (SPSS
Inc., Cary, NC, USA). Data distribution was analyzed using Shapiro-Wilk
Test to determine whether the data had a normal distribution. For the
analysis of continuous data, Student's t-test was used for normally
distributed variables and Kruskal-Wallis for non-parametric variables.
Chi-Square or Fisher's test were utilized for analysis of categorical
variables. A two-sided p value \textless{}0.05 was considered
statistically significant. All presented means are accompanied by their
respective standard deviations.

\textbf{Results}

\emph{Patients and clinical features}

A total of 140 patients with NPC were treated in our hospital throughout
the study period. Of them, only 73 patients had detailed documentation
of their clinical and radiographic examination of their middle ear
status on presentation and follow up and were thus included in our
study. The mean age of patients was 54.92 (range 18.8 to 79.67 years)
and the majority were male (71.2\%). 32 patients were smokers (43.8\%).
Most patients had an advanced disease at primary site at presentation
with 31 patients (42.5\%) presenting as T4 and 16 as T3 disease
(21.9\%). Fifty-eight (79.5\%) patients presented with nodal disease
(79.5\% were N1 and greater) and five patients (6.8\%) presented with a
metastatic disease as presented in Table 1. The median follow-up time
was 4.98 years (range 1-16.8 years) following completion of treatment.

Out of the 73 patients, 17 were treated using 2D/3D-CRT and 56 with
intensity-modulated radiation therapy (IMRT). The mean radiation dose
delivered to the primary site was 68.99 Gy (range 60 to 72 Gy). 70
patients (95.9\%) received concurrent chemotherapy. The remaining 3
patients presented with an early-stage disease (2 patients with T1 and
one with T2) with N0 and were treated with definitive RT with no
chemotherapy.

\emph{Pathology and immunohistochemistry}

Thirty-nine (53.4\%) patients had a non-keratinizing undifferentiated
(WHO- 3 classification) on their pathological examination, followed by
32 (43.8\%) patients with non-keratinizing differentiated disease (WHO-
2), and only two patients presented with a keratinizing NPC (2.7\%)
(WHO- 1). EBER staining for the presence of Epstein Barr Virus (EBV) was
positive in 38 samples (52.1\%). Proliferation marker Ki-67 was
58.6\%\selectlanguage{ngerman}±22.7\% in our study.

\emph{Middle ear status at NPC diagnosis}

At the time of NPC diagnosis 14 patients (19.2\%) presented with middle
ear effusion. When comparing the T stage at presentation, 85.7\% of
patients who presented with effusion were with an advanced T stage
(stages 3,4) compared to only 60.4\% in the non-effusion group (P value
of 0.07). Following radiotherapy, 7 patients had a resolution of their
MEE. Analysis of histopathological factors between patients with MEE at
presentation and those without found no difference in EBV status or
Ki-67 between groups.

\emph{Post radiation middle ear status}

Of the 59 patients presenting without effusion, eighteen patients
(24.6\%) eventually developed unilateral persistent post radiation MEE
with only one patient of the 59 who developed bilateral MEE and was
excluded. Risk factors for post radiation MEE were investigated and are
presented in Table 2. Demographic parameters such as patient sex and
age, T stage of primary tumor, pathological characteristics of the tumor
and radiation dosage were not associated with the occurrence of post
radiation MEE as compared with patients who did not develop MEE.

Interestingly the radiation modality whether 2D/3D-CRT or with
intensity-modulated radiation therapy (IMRT) had no correlation with
development of MEE.

Similarly, radiation doses to the middle ear, ET, LVP and TVP were also
not different between these groups. Furthermore, comparison between ears
with MEE to ears without MEE in patients who developed unilateral post
radiation MEE, did not reveal any difference in radiation doses to the
middle ear, ET, LVP and TVP.

\emph{Discussion}

In this study, no risk factors for post radiation MEE in NPC patients
were identified. Including specifically, radiation doses to the
eustachian tube, TVP and LVP muscles.

Much progress was made in the last decades in the treatment of NPC.
Today the primary treatment is RT, mainly IMRT, for early-stage NPC, and
a combination of concurrent platinum-based chemotherapy with RT for
locoregional advanced disease.\textsuperscript{11}

Since introduced, it is well known that radiation treatment for NPC is
associated with various morbidities and in particular otologic
complications, due to the inclusion of the temporal bone in the
radiation fields.\textsuperscript{3,4,12--14}

Previous studies demonstrated a wide range of data regarding the
prevalence of MEE in irradiated patients. 8\% to 48\% of NPC patients
undergoing conventional radiotherapy develop persistent or recurrent
post irradiation MEE.\textsuperscript{4,9,12,15}

In our study fourteen patients (19.2\%) presented with MEE at disease
diagnosis. Following radiotherapy, in half of these patients a
resolution of their MEE was noted. Post radiation persistent MEE was
observed in a quarter (24.6\%) of patients.

Interestingly, advanced T stage, which has been observed to be risk
factor for MEE at presentation due to association with skull base and
pterygoid plates invasion adjacent to the ET and its dilating muscles,
was not identified to be such a risk factor for post radiation MEE in
our study. Similar findings were also observed in the study by Chung-Han
Hsin et. al.\textsuperscript{18}, examining post-irradiated ears in 105
patients with NPC treated with RT.

Unlike previous studies, we also performed an analysis of
histopathological factors, including tumor histopathology, EBV tumor
staining and Ki-67 marker. We did not identify these features to be risk
factors for post radiation MEE as well as for MEE at NPC diagnosis.

Surprisingly, although modern radiotherapy techniques (IMRT) are
considered more precise and with minimized collateral damage, previous
studies\textsuperscript{16--18} as well as our current study showed no
protective effect against post irradiation MEE with IMRT compared to
3D-CRT. 31\% of patients treated with IMRT developed MEE similar to
29.4\% in the 3D-CRT group (p=0.9).

The etiology of post radiation MEE is hypothesized to be associated with
either obstruction or functional impairment of the eustachian tube;
and/or middle ear mucosal injury.\textsuperscript{14,19,20} Middle ear
mucosal injury is thought to be related to radiation-induced toxicity
leading to impairment of the mucosal and ciliary
function.\textsuperscript{14,21,22} Radiation injury to the
cartilaginous eustachian tube may cause synechia formation and fibrosis,
leading to physical obstruction of the ET. Alternatively, irradiation of
the muscles involved in the patency and dilatation of the ET -- Levator
veli palatini and more importantly the Tensor veli palatini may lead to
their atrophy or fibrosis. Previous studies focused on radiation doses
to the NP, the middle ear itself and the ET\textsuperscript{16-18} as
risk factors for post radiation MEE, but none thus far examined
radiation doses to the ET muscles.

In this study, analysis of radiation doses showed no correlation or
difference between the delivered dose to the ET, LVP and TVP and
development of MEE.

Previous studies suggested that radiation doses of 80Gy and higher are
associated with middle ear injury\textsuperscript{21,22}. However, these
doses exceed the conventional therapeutic doses. In our study,
examination of the radiation doses delivered to the middle ear itself
demonstrated no difference between patients who developed MEE and those
who did not. In addition, the doses delivered to the middle ears in this
study were far from the toxic level reported in previous publications.

Of note, our study results may be limited due to our cohort size and the
study's retrospective nature with the inherent biases. Nonetheless, it
provides a comprehensive analysis of patient, tumor and treatment
factors and their association with the development of post radiation
MEE, and the first to our knowledge, to examine tumor parameters and the
radiation doses delivered to the muscles involved in the patency of the
ET.

In conclusion, no risk factors for postirradiation MEE were identified,
including total radiation doses and specific doses to the middle ear, ET
and ET muscles. Thus, all NPC patients receiving treatment should be
evaluated for post radiation MEE and receive appropriate treatment when
necessary. Further studies are needed to understand the risk factors and
pathophysiology of post radiation MEE in NPC patients\textbf{.}

\textbf{Author Disclosure Statement}

No competing financial interests exist.





\textbf{References}

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2. Baujat B, Audry H, Bourhis J, et al. Chemotherapy as an adjunct to
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3. Ondrey FG, Greig JR, Herscher L. Radiation dose to otologic
structures during head and neck cancer radiation
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4. Yeh SA, Tang Y, Lui CC, Huang YJ, Huang EY. Treatment outcomes and
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5. Shah N. Otitis media and its sequelae. \emph{J R Soc Med} . Published
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6. Rosenfeld RM, Kay D. Natural history of untreated otitis
media.\emph{Laryngoscope} . Published online 2003.

7. Hunt MA, Zelefsky MJ, Wolden S, et al. Treatment planning and
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8. Teo PML, Ma BBY, Chan ATC. Radiotherapy for nasopharyngeal carcinoma
- Transition from two-dimensional to three-dimensional
methods.\emph{Radiother Oncol} . Published online 2004.

9. Lee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in
the treatment of nasopharyngeal carcinoma: An update of the UCSF
experience. \emph{Int J Radiat Oncol Biol Phys} . Published online 2002.

10. McMillan AS, Pow EHN, Kwong DLW, et al. Preservation of quality of
life after intensity-modulated radiotherapy for early-stage
nasopharyngeal carcinoma: Results of a prospective longitudinal
study.\emph{Head Neck} . Published online 2006.

11. Chen Y-P, Chan ATC, Le Q-T, Blanchard P, Sun Y, Ma J. Nasopharyngeal
carcinoma. \emph{Lancet (London, England)} . 2019;394(10192):64-80.

12. Bhandare N, Antonelli PJ, Morris CG, Malayapa RS, Mendenhall WM.
Ototoxicity after radiotherapy for head and neck tumors. \emph{Int J
Radiat Oncol Biol Phys} . 2007;67(2):469-479.

13. Jereczek-Fossa BA, Zarowski A, Milani F, Orecchia R.
Radiotherapy-induced ear toxicity. \emph{Cancer Treat Rev} .
2003;29(5):417-430.

14. Lambert EM, Gunn GB, Gidley PW. Effects of radiation on the temporal
bone in patients with head and neck cancer. \emph{Head Neck} .
2016;38(9):1428-1435.

15. Kew J, King AD, Leung SF, et al. Middle ear effusions after
radiotherapy: correlation with pre-radiotherapy nasopharyngeal tumor
patterns. \emph{Am J Otol} . 2000;21(6):782-785.

16. Liang K-L, Hsin C, Chen T, Liang K. Postirradiation otitis media
with effusion in nasopharyngeal carcinoma patients treated by
intensity-modulated radiotherapy. \emph{Laryngoscope} .
2013;123(9):2148-2153.

17. Liang K-L, Su M-C, Twu C-W, Jiang R-S, Lin J-C, Shiao J-Y. Long-term
result of management of otitis media with effusion in patients with
post-irradiated nasopharyngeal carcinoma. \emph{Eur Arch
oto-rhino-laryngology Off J Eur Fed Oto-Rhino-Laryngological Soc Affil
with Ger Soc Oto-Rhino-Laryngology - Head Neck Surg} .
2011;268(2):213-217.

18. Hsin C-H, Chen T-H, Young Y-H, Liu W-S. Comparison of otologic
complications between intensity-modulated and two-dimensional
radiotherapies in nasopharyngeal carcinoma patients. \emph{Otolaryngol
neck Surg Off J Am Acad Otolaryngol Neck Surg} . 2010;143(5):662-668.

19. Zhao L, Chen H, Hu B, Zhang H, Lin Q. Prognostic significance of
Ki67 expression and the derived neutrophil-lymphocyte ratio in
nasopharyngeal carcinoma. \emph{Cancer Manag Res} . 2018;10:1919-1926.

20. Young YH, Lin KL, Ko JY. Otitis media with effusion in patients with
nasopharyngeal carcinoma, postirradiation. \emph{Arch Otolaryngol Head
Neck Surg} . 1995;121(7):765-768.

21. Ohashi Y, Nakai Y, Esaki Y, Ikeoka H, Koshimo H, Onoyama Y. Acute
effects of irradiation on middle ear mucosa. \emph{Ann Otol Rhinol
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Table 1 -- Demographic and clinical data\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{Parameter}\strut
\end{minipage} & \begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{Mean/\%}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Total number of patients\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
73\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Age (Mean, Years)\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
54.88 (18.8-79.67)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Gender (Male)\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
52 (71.2\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Smokers (Yes)\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
54 (43.8\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
T Classification\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
10 (13.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
16 (21.9\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
16 (21.9\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
31 (42.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
N Classification\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
15 (20.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
29 (39.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
21 (28.8\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
8 (11\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
M Classification\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
67 (93.2\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
5 (6.8\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Stage\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2 (2.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
14 (19.2\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
23 (31.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
4a\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
29 (39.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
4b\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
5 (6.8\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
EBV\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Positive\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
38 (52.1\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Negative\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
35 (47.9\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
WHO Classification 1 -- Keratinizing\\
2 -- Non-Keratinizing Differentiated\\
3 -- Non-Keratinizing Undifferentiated\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
2 (2.7\%) 32 (43.8\%) 39 (53.4\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
MEE\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
At presentation\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
14 (19.18\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Post irradiation (Excluding MEE at presentation)\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
18 (24.66\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Radiation type\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
IMRT\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
56 (76.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
EBR\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
17 (23.3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Follow-up time (Median, Years)\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
4.98 (1-16.8)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* Numbers are presented as means, (corresponding percentage)

** Abbreviations -- EBV -- Epstein-Barr Virus; WHO - World Health
Organization; MEE -- Middle ear effusion; IMRT - intensity-modulated
radiotherapy; EBR -- External Beam radiation;

Table 2 -- Comparison of patients with and without effusion during study
period\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Parameter\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
No MEE throughout the study period (n=41)\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Post radiation MEE (n=18)\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
P Value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age (Years)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
55.37\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
59.21\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.29\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex -- Male n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
29 (70.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12 (66.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.77\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Advanced T Stage 3-4 n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27 (65.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (61.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.73\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Smoker n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17 (41.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (44.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.83\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Radiation Treatment - IMRT n(\%)***\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
29 (70.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (72.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.91\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
WHO Classification\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.17\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Type 1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (4.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 (0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Type 2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22 (53.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (33.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Type 3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
17 (41.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
12 (66.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
EBV n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
21 (51.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.93\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PTV (Gy)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
64.79\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
64.07\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.99\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
GTV (Gy)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
68.13\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
66.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.94\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CTV (Gy)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
65.09\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
64.84\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.78\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Middle Ear (Gy)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
42.61\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
45.83\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.58\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Tensor Veli Palatini (Gy)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
63.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
62.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Levator Veli Palatini (Gy)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
64.26\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
63.54\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.52\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Eustachian Tube (Gy)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
48.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
51.94\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.37\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* Numbers are presented as means, (corresponding percentage)

** Abbreviations -- EBV -- Epstein-Barr Virus; WHO - World Health
Organization; IMRT - intensity-modulated radiotherapy; EBR -- External
Beam radiation; GTV - gross target volume; CTV - clinical target volume;
PTV - patient target volume

*** IMRT data is compared to EBR in the analysis presented in the table.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Tables.docx`  available at \url{https://authorea.com/users/400021/articles/641014-post-radiation-middle-ear-effusion-in-npc-patients-analysis-of-patient-tumor-and-radiation-factors}

\selectlanguage{english}
\FloatBarrier
\end{document}

